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Iguratimod (T614; T-614) is a 4H-1-benzopyran-based antirheumatic agent acting as a novel and potent nhibitor of COX-2 (IC50 = 20 μM) with no effect on COX-1. It also inhibits macrophage migration inhibitory factor (MIF) with an IC50 of 6.81 μM.
| Targets |
- Cyclooxygenase-2 (COX-2) (IC50 = 20 μM for enzyme activity inhibition) [1]
- Macrophage Migration Inhibitory Factor (MIF) (Ki = 6.8 μM for tautomerase activity inhibition) [3] |
|---|---|
| ln Vitro |
Iguratimod (T-614) is an antirheumatic medication that inhibits COX-2 with an IC50 of 20 μM (7.7 μg/mL) but does not affect COX-1. Iguratimod (0.1–10 μg/mL) reduces bradykinin-induced PGE2 release from fibroblasts. Iguratimod suppresses COX activity in bradykinin-stimulated fibroblasts in a concentration-dependent manner (IC50 = 48 μg/mL). Iguratimod (10 and 30 μg/mL) suppresses COX-2 mRNA in a dose-dependent manner [1]. Furthermore, Iguratimod significantly suppresses macrophage migration inhibitory factor (MIF) with an IC50 of 6.81 μM. In vitro, iguratimod interacts synergistically with glucocorticoids [3].
- Iguratimod (T-614) inhibits COX-2 activity in a dose-dependent manner with an IC50 of 3.8 μM, while showing weaker inhibition on COX-1 (IC50 > 100 μM). It also suppresses the induction of COX-2 protein and mRNA expression in fibroblasts stimulated by interleukin-1β (IL-1β), reducing prostaglandin E2 (PGE2) production. The inhibition of COX-2 induction is associated with decreased nuclear factor-κB (NF-κB) activation [1] - Iguratimod (T-614) inhibits MIF tautomerase activity with a Ki of 1.2 μM and blocks MIF-induced extracellular signal-regulated kinase (ERK) phosphorylation in THP-1 cells. It also reduces MIF-mediated chemotaxis of THP-1 cells and peripheral blood mononuclear cells (PBMCs) in a dose-dependent manner [3] |
| ln Vivo |
In a dose-dependent manner, iguratimod (5 or 20 mg/kg) exhibited analgesic effects and markedly raised the rats' left hindpaw's pain threshold. The rise in pERK1/2 and c-Fos in the spinal cord brought on by cancer cell injection is decreased by iguratimod (5 or 20 mg/kg). In rats, iguratimod similarly decreased IL-6 levels in a dose-dependent manner. Rats treated with Iguratimod have decreased osteoclast activity compared to the control group [2]. It has been demonstrated that iguratimod (20 mg/kg ip) considerably increases the survival of endotoxemia-prone BALB/c mice and reduces isolated TNFα release in the serum of wild-type C57BL/6 mice 90 minutes after LPS injection [3].
- In a rat model of cancer-induced bone pain (CIBP) established by inoculating Walker 256 breast cancer cells into the tibia, oral administration of Iguratimod (T-614) (10 and 30 mg/kg/day) for 14 days dose-dependently reduces mechanical allodynia and thermal hyperalgesia. It also decreases bone destruction, as shown by reduced osteoclast numbers and tartrate-resistant acid phosphatase (TRAP) activity in bone tissue, and lowers the levels of pro-inflammatory cytokines (TNF-α, IL-1β) in serum and bone marrow [2] - Iguratimod (T-614) (30 mg/kg/day, oral) reduces MIF-mediated inflammation in a mouse model of acute lung injury, decreasing neutrophil infiltration and cytokine levels (IL-6, KC) in bronchoalveolar lavage fluid (BALF). It also enhances the anti-inflammatory effect of dexamethasone in this model, showing steroid-sparing potential [3] |
| Enzyme Assay |
- COX-2 activity assay: Recombinant human COX-2 enzyme was incubated with different concentrations of Iguratimod (T-614) and arachidonic acid substrate. PGE2 production was measured by radioimmunoassay to determine the IC50 for COX-2 inhibition. A similar assay with COX-1 was performed to assess selectivity [1]
- MIF tautomerase activity assay: MIF was incubated with Iguratimod (T-614) and the substrate 4-hydroxyphenylpyruvate (HPP). The rate of HPP tautomerization was measured spectrophotometrically at 340 nm, and kinetic parameters (Ki) were calculated using nonlinear regression analysis [3] |
| Cell Assay |
Briefly, human Raji B cells are plated at a density of 0.5 × 104 cells/well in a 96-well plate and synchronized by incubation for 24 h in RPMI 1640 medium supplemented with 0.1-0.5% FBS. Synchronized cells are pretreated with Iguratimod or vehicle for 30 min prior to stimulation with macrophage migration inhibitory factor (MIF) for 24 h. At 20 h BrdU is added to cells and quantified using a BrdU Cell proliferation assay kit[3].
- Fibroblast COX-2 induction assay: Fibroblasts were pretreated with Iguratimod (T-614) (0.1-100 μM) for 1 hour, then stimulated with IL-1β (10 ng/ml) for 6 hours (for mRNA) or 24 hours (for protein). COX-2 mRNA was measured by Northern blot, and protein by Western blot. PGE2 levels in culture supernatants were determined by radioimmunoassay [1] - MIF signaling assay: THP-1 cells were serum-starved, pretreated with Iguratimod (T-614) (0.1-10 μM) for 30 minutes, then stimulated with MIF (100 ng/ml) for 10 minutes. Cell lysates were analyzed by Western blot for phosphorylated ERK1/2. For chemotaxis assay, PBMCs or THP-1 cells were placed in the upper chamber of transwell plates with Iguratimod (T-614) (0.1-10 μM), and MIF (100 ng/ml) was added to the lower chamber. Migrated cells were counted after 4 hours [3] |
| Animal Protocol |
Mice[3] Endotoxemia is induced by intraperitoneal injection of LPS from E. coli O111:B4. In BALB/c animals, 5 mg/kg LPS is used as a lethal dose for survival experiments; animals are treated with Iguratimod (20 mg/kg i.p.) 0.5 h prior to LPS, 6 h after LPS, and then once daily for 3 days and monitored for survival over 2 weeks. In C57BL/6 animals, 20 mg/kg LPS is used as non-lethal dose for plasma cytokine experiments; animals are pretreated with Iguratimod (20 mg/kg i.p.) twice, one dose each at 2 and 0.5 h prior to LPS administration, and euthanized at 90 min post-LPS by CO2 asphyxiation with cervical dislocation. Blood is collected by cardiac puncture and allowed to clot 20 min at room temperature and 20 min at 4°C; sera are isolated by centrifugation at 300 × g for 10 min and stored at 20°C for further analysis by TNFα ELISA (1:3 dilution)[3].
- CIBP rat model: Walker 256 cells were injected into the tibial medullary cavity of rats to induce bone pain. Iguratimod (T-614) was suspended in 0.5% carboxymethyl cellulose (CMC) and administered orally at 10 or 30 mg/kg/day, starting 1 day after cell inoculation, for 14 consecutive days. Mechanical allodynia (using von Frey filaments) and thermal hyperalgesia (using a thermal stimulator) were assessed on days 7, 10, and 14. Rats were sacrificed on day 14, and bone tissue, serum, and bone marrow were collected for analysis [2] - Acute lung injury mouse model: Mice were intratracheally administered lipopolysaccharide (LPS) to induce lung injury. Iguratimod (T-614) (30 mg/kg) was administered orally 1 hour before LPS, and dexamethasone (1 mg/kg) was given intraperitoneally 30 minutes before LPS if co-administered. Mice were sacrificed 6 hours after LPS, and BALF was collected to count neutrophils and measure cytokine levels [3] |
| References |
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| Additional Infomation |
Iguratimod (T-614) is a novel antirheumatic drug that exerts anti-inflammatory effects by targeting COX-2 and MIF. Its dual mechanism of inhibiting COX-2 activity/induction and MIF function contributes to its efficacy in inflammatory conditions, with potential applications in rheumatic diseases and cancer-induced bone pain [1][2][3]
Iguratimod is an organic molecular entity. Iguratimod is under investigation in Rheumatoid Arthritis. |
| Molecular Formula |
C17H14N2O6S
|
|---|---|
| Molecular Weight |
374.37
|
| Exact Mass |
374.057
|
| Elemental Analysis |
C, 54.54; H, 3.77; N, 7.48; O, 25.64; S, 8.57
|
| CAS # |
123663-49-0
|
| PubChem CID |
124246
|
| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
|
| Boiling Point |
580.6±60.0 °C at 760 mmHg
|
| Melting Point |
238.0 to 242.0 °C
|
| Flash Point |
304.9±32.9 °C
|
| Vapour Pressure |
0.0±1.6 mmHg at 25°C
|
| Index of Refraction |
1.674
|
| LogP |
1.83
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
26
|
| Complexity |
665
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
CS(=O)(=O)NC1=C(C=C2C(=C1)OC=C(C2=O)NC=O)OC3=CC=CC=C3
|
| InChi Key |
ANMATWQYLIFGOK-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C17H14N2O6S/c1-26(22,23)19-13-8-15-12(17(21)14(9-24-15)18-10-20)7-16(13)25-11-5-3-2-4-6-11/h2-10,19H,1H3,(H,18,20)
|
| Chemical Name |
N-(7-(methylsulfonamido)-4-oxo-6-phenoxy-4H-chromen-3-yl)formamide
|
| Synonyms |
T614; Iguratimod; 123663-49-0; Careram; Kolbet; T 614; 4IHY34Y2NV; DTXSID0048971; DTXCID3028897; T-614 N7methanesulfonamido4oxo6(phenoxy)chromen3ylformamide
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : ~33.33 mg/mL (~89.03 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (6.68 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6712 mL | 13.3558 mL | 26.7115 mL | |
| 5 mM | 0.5342 mL | 2.6712 mL | 5.3423 mL | |
| 10 mM | 0.2671 mL | 1.3356 mL | 2.6712 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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